Although vascularization occurs in the normal physiological state of humans and animals, such as during blastogenesis and ovulation or placenta formation in accordance with the female estrus cycle, as well as in the normal state during wound healing and in the healing process of inflammations and so on, it is also known to occur in numerous pathological states that cause rapid increases and expansion of capillaries resulting in serious tissue damage. For example, it is described in N. Engl. J. Med., 285: 1182, 1971 that the growth of tumor cells occurs dependent on an increase in capillary vascularization of tumor tissue. In addition, Matsubara, et al. reported in Jpn. J. Inflammation, Vol. 10, No. 4, July 1990, p. 241-245 that, during the course of an inflammation, there is a correlation between neogenesis of small blood vessels such as capillaries and postcapillary venules and cellular invasion by monocytes and lymphocytes, and neogenesis of small blood vessels as nutrient vessels is essential for granulation growth.
In addition, known examples of other diseases related to abnormal acceleration of vascularization include diabetic retinopathy, retrolental fibroplasia, vascularization accompanying corneal transplant, glaucoma, ophthalmic tumor and trachoma in the field of ophthalmology, angioma and fibrous angioma in the field of pediatrics, hypertrophic cicatrix and granulation in the field of surgery, rheumatoid arthritis and edemic scleroma in the field of internal medicine, and atherosclerosis and various types of tumors in the case of heart diseases.
Consequently, the use of drugs that inhibit vascularization as pharmaceuticals for the treatment of various types of the above diseases has recently attracted attention. Namely, neogenesis of small vessels is known to occur during the course of disease. For example, drugs having vascularization inhibitory effects are useful in the treatment of various diseases such as cancer, chronic inflammations such as chronic rheumatoid arthritis, diabetic retinopathy, pronatal retinopathy, various thrombotic diseases within the retina, arteriosclerosis, angioma, angiofibroma and psoriasis.
Tetrahydrocortisol is disclosed in, for example, the above-mentioned Jpn. J. Inflammation, Vol. 10, No. 4, July 1990, p. 241-245 as an example of a drug having vascularization inhibitory effects. In addition, several anti-rheumatic agents used in the treatment of chronic rheumatoid arthritis are disclosed as also having vascularization inhibitory effects. Examples of these anti-rheumatic agents include SH compounds such as gold sodium thiomaleate, auranofin and D-penicillamine.
However, drugs having vascularization inhibitory effects as described above also have various clinical problems. For example, it is necessary for tetrahydrocortisol to be used concomitant to heparin, which has vascularization promotion effects, in order for it to demonstrate vascularization inhibitory effects.
On the other hand, many of the anti-rheumatic agents having the vascularization inhibitory effects described above have serious adverse side effects, making their application difficult in terms of managing their administration.
In consideration of these problems of the prior art, the present invention provides a novel compound having remarkable vascularization inhibitory effects unaccompanied by serious adverse side effects, which is useful for the treatment and prevention of various diseases accompanied by abnormal acceleration of vascularization, along with a vascularization inhibitor having for its active ingredient said compound.